Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, ischemic diseases and certain neurodegenerative disorders [see generally Science, 281, pp. 1283-1312 (1998); Ellis et al., Ann. Rev. Cell. Biol., 7, p. 663 (1991)].
Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly [N. A. Thornberry, Chem. Biol., 5, pp. R97-R103 (1998)]. These signaling pathways vary depending on cell type and stimulus, but all apoptosis pathways appear to converge at a common effector pathway leading to proteolysis of key proteins. Caspases are involved in both the effector phase of the signaling pathway and further upstream at its initiation. The upstream caspases involved in initiation events become activated and in turn activate other caspases that are involved in the later phases of apoptosis.
The utility of caspase inhibitors to treat a variety of mammalian disease states associated with an increase in cellular apoptosis has been demonstrated using peptidic caspase inhibitors. For example, in rodent models, caspase inhibitors have been shown to reduce infarct size and inhibit cardiomyocyte apoptosis after myocardial infarction, to reduce lesion volume and neurological deficit resulting from stroke, to reduce post-traumatic apoptosis and neurological deficit in traumatic brain injury, to be effective in treating fulminant liver destruction, and to improve survival after endotoxic shock [H. Yaoita et al., Circulation, 97, pp. 276-281 (1998); M. Endres et al., J. Cerebral Blood Flow and Metabolism, 18, pp. 238-247, (1998); Y. Cheng et al., J. Clin. Invest., 101, pp. 1992-1999 (1998); A. G. Yakovlev et al., J. Neurosci., 17, pp. 7415-7424 (1997); I. Rodriquez et al., J. Exp. Med., 184, pp. 2067-2072 (1996); Grobmyer et al., Mol. Med., 5, p. 585 (1999)]. However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacological properties, such as poor cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism [J. J. Plattner and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126]. This has hampered their development into effective drugs. These and other studies with peptidic caspase inhibitors have demonstrated that an aspartic acid residue is involved in a key interaction with the caspase enzyme [K. P. Wilson et al., Nature, 370, pp. 270-275 (1994); Lazebnik et al., Nature, 371, p. 346 (1994)].
Accordingly, peptidyl and non-peptidyl aspartic acid compounds are useful as caspase inhibitors. For examples, WO96/03982 reports azaaspartic acid analogs effective as interleukin-1β converting enzyme (“ICE”) inhibitors.
However, due to their acidic nature such peptidic and non-peptidyl aspartic acid derivatives are charged at physiological pH. This has inhibited their ability to cross the blood brain barrier and to penetrate cells at therapeutically useful levels.
Accordingly, it would be advantageous to have drug derivatives that are targeted at the diseased organs, especially the brain and central nervous system. In addition, it would be advantageous to have drug derivatives that are targeted at the diseased cells rather than at healthy cells, thus reducing undesirable side-effects.
The use of prodrugs to impart desired characteristics such as increased bioavailability or increased site-specificity for known drugs is a recognized concept. The use of pro-drugs to deliver compounds across the Blood-Brain barrier (BBB) is also well known. Bradley D. Anderson, “Prodrugs for Improved CNS Delivery” in Advanced Drug Delivery Reviews (1996), 19, 171-202 provides a review of the area. In particular, the use of alkyl esters of chloambucil have been used to enhance brain penetration (Cancer Chemother. Pharmacol. (1990), 25, 311-319); the use of benzoyl esters of dopamine have been used to enhance delivery across BBB (Naunyn-Schmiedeberg's Arch. Pharmacol., (1988), 338(5), 497-503); lipophilic esters of a leucine-enkephalin analogue have been used for brain-targeted delivery (J. Med. Chem., (1996), 39(24), 4775-4782). Disulphide-based esters of L-DOPA have been shown to increase brain levels of DOPA in the rat brain up to 30 fold (Int. J. Pharmaceutics, (1995), 116, 51-63). The tyrosine ester of nipecotic acid showed in vivo effects consistent with BBB penetration (J. Pharma. Sci., (1999), 88(5), 561) and D-glucose esters of 7-chlorokynurenic acid are available to CNS and are anti-convulsive in vivo (Brain Res., (2000), 860, 149-156.
A need nevertheless exists for prodrugs of caspase inhibitors that have the ability to cross the blood brain barrier and penetrate the brain and central nervous system at therapeutically useful levels.